Molecular regulation of dendritic spines in schizophrenia

精神分裂症树突棘的分子调控

基本信息

批准号：
8197803
负责人：
GLENN THOMAS KONOPASKE
金额：
$ 18.03万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197803
关键词：
3-Dimensional AGTR2 gene Actins Affect Animal Model Antipsychotic Agents Area Bipolar Disorder Chronic Chronic Disease Cognitive deficits Cytoskeleton Data Dendritic Spines Drug Exposure Ensure Functional disorder Gene Expression Generations Genes Goals Haloperidol IGF1R gene In Situ Hybridization Intraperitoneal Injections Label Lead Life MARCKS gene Measurement Mentored Clinical Scientist Award Mentorship Messenger RNA Microscopy Molecular Molecular Target Neocortex Neurons Neurosciences Pathology Pharmaceutical Preparations Play Population Prefrontal Cortex Probability Process Proteins Psychiatrist Publishing Pyramidal Cells Rattus Regulation Role Safety Saline Schizophrenia Site Statistical Methods Testing Time Vertebral column Western Blotting base career cohort density disability improved mRNA Expression neuropathology neurotransmission novel olanzapine professor programs protein expression public health relevance reconstruction research study skills

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia is a common, devastating illness, which most often leads to life long disability. Greater understanding of schizophrenia's pathophysiology might lead to novel medications with improved safety and efficacy. Dendritic spines are the chief site of excitatory neurotransmission in the neocortex and their reduction on deep layer III pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia might contribute to the cognitive deficits observed in the illness. In this K08 Mentored Clinical Scientist Award, the candidate will test the general hypothesis that a reduction of dendritic spines in the DLPFC of subjects with schizophrenia might be associated with alterations in the mRNA and protein expression of PTPRF, AGTR2, IGF1R, MARCKS, PPP1R9A, and ARHGEF2. These 6 genes regulate dendritic spines and preliminary data suggests their mRNA expression is altered in schizophrenia. While investigating these hypotheses, the candidate, a general psychiatrist, will undertake a program of study in 1) 3-D reconstructions of neurons and their processes, Western Blots, and duallabel immunofluorescent microscopy, 2) the use of Quantitative Real-Time PCR (QRT-PCR) and in situ hybridization, 3) the molecular mechanisms which regulate dendritic spines and contribute to their loss in schizophrenia, 4) advanced statistical methods as they apply to neuroanatomical and gene expression data; and 5) relevant areas of neuroscience as they apply to the pathophysiology of schizophrenia. Acquiring these skills under the mentorship of Professors Francine M. Benes, and Joseph T. Coyle will enable the candidate to launch an independent career investigating the pathophysiology of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a devastating chronic disease affecting 1% of the population worldwide, and despite recent advances in treatment, schizophrenia often produces life-long disability. The goal of the proposed experiments is to better understand the molecular and cellular alterations associated with the illness with the hope that molecular targets will be identified for novel medications having improved efficacy and safety.

描述（由申请人提供）：精神分裂症是一种常见的毁灭性疾病，通常导致生命长期残疾。对精神分裂症的病理生理学的更多了解可能会导致新型药物，并提高安全性和有效性。树突状棘是新皮层中兴奋性神经传递的主要部位，并且在精神分裂症的背外侧前额叶皮层（DLPFC）中的深层III锥体细胞中它们的减少可能有助于在疾病中观察到的认知缺陷。在这项K08指导的临床科学家奖中，候选人将检验一个普遍的假设，即患有精神分裂症受试者DLPFC的树突状刺可能与PTPRF，AGTR2，IGF1R，IGF1R，MARCKS，PPP1R9A和ARHGEF2的mRNA和蛋白质表达的改变可能有关。这6个基因调节了树突状刺，初步数据表明它们的mRNA表达在精神分裂症中发生了改变。在研究这些假设的同时，候选人是一名普通精神病医生，将在1）中进行研究计划1）1）神经元的3-D重建及其过程及其过程，蛋白质印迹和Duallabel免疫荧光显微镜，2）使用定量实时PCR（QRT-PCR），并在当地造成了定量的杂交机制，并在其上造成了这些损失，该机制构成了这些杂种，该机制构成了分类的构成，该机构是分类的，精神分裂症，4）用于神经解剖学和基因表达数据的高级统计方法； 5）神经科学的相关领域，因为它们适用于精神分裂症的病理生理。在Francine M. Benes教授和Joseph T. Coyle的指导下获得这些技能，将使候选人能够启动一个独立的职业，调查精神分裂症的病理生理学。公共卫生相关性：精神分裂症是一种毁灭性的慢性疾病，影响了全球1％的人口，尽管最近的治疗进展，精神分裂症仍会导致终身残疾。提出的实验的目的是更好地了解与疾病相关的分子和细胞改变，希望能够确定分子靶标的用于提高功效和安全性的新型药物。